A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Nociception
Nociception may be defined as the neural processes of encoding and processing noxious stimuli. Of particular interest are anti-nociceptive drugs that act peripherally. By “anti-nociceptive”, it is meant that the drug suppresses the psychical and physiological perception of noxious stimuli. By “peripherally”, it is meant that the primary site of the drug action is located outside the central nervous system, that is, outside of the brain and spinal cord.
There are currently two major classes of anti-nociceptive drugs that act peripherally to attenuate transmission of nociceptive (noxious) signals to the central nervous system. One class is local anesthetics, such as procaine and lidocaine, which act on peripheral nerve fibers to inhibit nerve conduction of nociceptive signals towards the central nervous system.
Another class is agents such as aspirin and ibuprofen that inhibit the synthesis of certain prostaglandins. These prostaglandins, when released by tissues during injury or inflammation, lower the threshold for firing of sensory nerve fibers that respond to noxious stimuli. Yet another class of anti-nociceptive drugs is the narcotic analgesics, which do not suppress pain via peripheral actions but instead act directly on neuronal elements in the brain and spinal cord.
Pain, defined by Sir Charles Sherrington as “the psychical adjunct of an imperative protective reflex”, is activated by increased discharge of unmyelinated small-diameter sensory fibers called polymodal C fibers. Pain is categorized as nociceptive or neuropathic. Nociceptive pain is caused by cell injury and neuropathic pain is caused by damage to the nerve fibers that transmit the pain signals. There are many conditions that produce pain; the most common being, for example, trauma, inflammation, and immune disorders. Sensations that may accompany pain are irritation, pruritus (itch), and a sense of malaise and disaffection. As used herein, the psychical adjuncts of nociception are together categorized as “sensory discomfort”.
There are four basic types of animal tissues: connective tissue, muscle tissue, nervous tissue and epithelial tissue. Epithelial cells line cavities and surfaces of organs throughout the body. When the layer is one cell thick, it is called simple epithelium. If there are two or more layers of cells, it is called stratified epithelium. Stratified epithelium is composed mainly of squamous (flattened) cells and some cuboidal cells. In the skin, external lip, and tongue, the exterior layer of cells of stratified epithelium are dead and become a tough, water-impermeable protein called keratin. Stratified squamous epithelia which do not contain keratin are present on the ocular surfaces including the margin of the eyelid, the anterior part of the eyeball, the conjunctiva, the lachrymal system, the pre-corneal film, and the cornea; the lining of the oral cavity including the internal portion of the lips; the pharyngeal surface; the esophageal surface; and the anogenital surface. Keratinized tissues withstand injury better than non-keratinized tissues. Non-keratinized epithelial surfaces must be kept moist by glandular (serous and mucous) secretions in order to prevent desiccation.
Current topical anti-nociceptive (pain-suppressant) compounds have limited efficacy on pain from non-keratinized stratified epithelium (NKSE). This is especially true for sensory discomfort from the ocular surfaces.
Local anesthetic compounds such as lidocaine are used for pain and discomfort from anogenital surfaces (e.g., for vulvovaginal pain) and from the pharynx (e.g., for cough and pharyngitis) but these drugs can cause hypersensitivity reactions and have the undesirable property of numbing the tissues to touch and pressure. Local anesthetics can be used in an emergency for pain from the ocular surfaces, especially corneal pain, but prolonged use is dangerous because this class of drugs inhibits epithelial cell growth.
The non-steroidal anti-inflammatory compounds (NSAIDs), for example, ketorolac, can be used on the ocular surface for a short period time, for example, to reduce the acute pain of cataract surgery, but not for prolonged use on the eye. Topical NSAIDs do not work for pain arising from anogenital or oral cavity NKSE.
Menthol has some limited analgesic action in ointments for hemorrhoidal discomfort. In lozenges and confectionery, menthol has some benefit for sore or irritated throats and for cough. Menthol is highly irritating to the eyes but is used in some eye drops in Japan. On keratinized skin, high concentrations of menthol (for example, more than 2% by weight) can be applied without direct irritation to the skin. For example, topical patches containing 5% by weight menthol (e.g., IcyHot Medicated Patch; Chattem, Inc.) can be applied onto the skin of the torso to relieve muscular pain. On non-keratinized epithelia, however, the irritating effects of menthol limit its use; for example, lozenges containing more than 8 mg of menthol per unit are aversive in taste.
There is a need for a new class of pharmacological agent that can suppress sensory discomfort arising from NKSE but without the problems of irritancy and toxicity.
Watson et at, “Compounds with the Menthol Cooling Effect”, J. Soc. Cosmet. Chem., Vol. 29, pp. 185-200, 1978, describes a number of compounds with physiological cooling effects on keratinized epithelia such as the skin and the tongue. The studies described therein provide a background for the discovery of other compounds with more selective actions on NKSE.
Watson et al., 1979, “N-Substituted paramenthane carboxamides”, U.S. Pat. No. 4,178,459 granted 11 Dec. 1979. describes “N-substituted paramenthane carboxamides” of the following formula. Among the examples therein are compounds where R′ is —H and R″ is —CH2C(═O)OCH3, —CH2C(═O)OCH2CH3, or —CH2C(═O)OCH2CH2CH3. The corresponding compound where R″ is —CH2C(═O)OCH(CH3)2 is not shown.
